JP6419159B2 - Injection device - Google Patents

Description

  The present invention is directed to a hand-held injection device, ie a drug delivery device for selecting and dispensing several user variable doses of medication.

  Pen drug delivery devices are regularly injected by people who have not received formal medical training. Such applications are becoming increasingly common among diabetic patients, and self-therapy allows such patients to effectively manage their own diabetes. Indeed, such a drug delivery device allows the user to individually select and dispense several user variable doses of medication. The present invention does not cover so-called fixed dose devices, which simply allow a given dose to be dispensed and do not increase or decrease the set dose.

  There are basically two types of drug delivery devices: resettable devices (ie, reusable) and non-resettable devices (ie, disposable). For example, disposable pen delivery devices are supplied as self-contained devices. Such self-contained devices do not have a detachable filled cartridge. Rather, the filled cartridge cannot be removed from these devices and replaced without destroying the devices themselves. Therefore, such a disposable device need not have a resettable dose setting mechanism. The present invention can be applied to both types of devices, namely disposable devices as well as reusable devices.

  Another segment of drug delivery device type relates to the drive mechanism: for example, a device that is manually driven by the user applying force to the injection button, a device that is driven by a spring, etc., and combining these two concepts There are devices, i.e. spring assisted devices, which still require the user to exert an injection force. Spring type devices include pre-loaded springs and springs that are loaded by the user during dose selection. Some stored energy devices use a combination of a pre-loaded load on the spring and additional energy provided by the user during dose setting, for example. In general, the present invention can be applied to all these types of devices, i.e. devices with or without drive springs.

  These types of pen delivery devices (named as they often resemble enlarged fountain pens) generally have three main elements: a cartridge that is often housed in a housing or holder A needle section connected to one end of the cartridge section; and a dosing section connected to the other end of the cartridge section. Cartridges (often referred to as ampoules) are usually at a reservoir filled with medication (eg, insulin), a movable rubber stopper or stopper at one end of the cartridge reservoir, and often at the other end that is constricted And a top having a pierceable rubber seal. A crimped annular metal band is typically used to hold the rubber seal in place. Cartridge housings can usually be made of plastic, but cartridge reservoirs have historically been made of glass.

  The needle assembly is typically a replaceable double-ended needle assembly. Prior to injection, a replaceable double-ended needle assembly is attached to one end of the cartridge assembly and the dose is set before the set dose is administered. Such a removable needle assembly can be attached or pressed (ie, clicked) onto the pierceable sealing end of the cartridge assembly.

  The dosing section or dose setting mechanism is usually the part of the pen device that is used to set (select) the dose. Upon injection, a spindle or piston rod contained in the dose setting mechanism pushes the stopper or stopper of the cartridge. This force causes the drug contained in the cartridge to be injected through the attached needle assembly. After injection, the needle assembly is removed and discarded as generally recommended by most drug delivery devices and / or needle assembly manufacturers and suppliers.

  Disposable drug delivery devices for selecting and dispensing several user-variable doses of medication according to the present invention typically include a housing, a cartridge holder for receiving the cartridge, a lead screw or piston rod, and a piston during dose dispensing. Means for driving the rod. Such a disposable drug delivery device is known, for example, from US Pat. The piston rod acting on the cartridge stopper is advanced by the driver during dose dispensing. The remaining dose in the cartridge is indicated to the user by the position of the stopper and the distal end of the piston rod in the cartridge. Especially for visually impaired users, it can be difficult to identify the dose remaining in the cartridge.

  U.S. Patent No. 6,053,836 discloses an injection device that includes a housing, an elastic member, and a dose setting member operably connected to a dose indicator barrel position located within the housing. The elastic member is a helical spring adapted to provide the necessary force in the axial direction of the injection device to expel the dose from the injection device. The dose setting member and the dose indicator barrel are movable relative to each other and cooperate to set the dose to be discharged from the injection device. The dose indicator barrel engages a threaded portion of the housing. During dose setting, the dose indicator barrel is adapted for compound rotational translation within the housing relative to the housing. The compound rotary translation of the dose indicator barrel is caused by a threaded interface between the dose indicator barrel and the housing. Generally, translation of the dose indicator barrel during dose setting will cause the indicator barrel to protrude from the housing depending on the amount of dose set, or the barrel will be covered with the housing independent of the set dose Where this is preferred, a relatively long housing is required.

  In addition, US Pat. No. 6,057,049 describes an injection device in which the force necessary to drain the dose from the injection device is established by hand, i.e. without the aid of a spring or the like. The device includes a housing, a first component for extruding the injection solution from the container, and a dosing member in threaded engagement with the first component. The dosing member can be rotated with the first component relative to the housing for the purpose of selecting the desired injection dosing. Further, the dosing member is threadedly engaged with a window sleeve that moves axially relative to the dosing member within the housing as the dosing member rotates. Several scales provided on the dosing member are visible through this window sleeve. A knob is provided that rotates during dose setting, which also moves axially simultaneously from the housing as the window sleeve translates out of the housing during dose setting. Thus, the dosing member does not translate during dose setting, but there are still components (knobs with window sleeves) protruding from the housing when the dose is set.

  U.S. Patent No. 6,057,836 discloses a preamble injection device according to claim 1 including a housing, a rotatable dose setting member, a power reservoir, a release member, a piston rod, and a rotatably arranged drive member. The drive member has two different axes: a first (dose setting) position when the dose setting member is in its dose setting position and a second (injection) position when the dose setting member is in its injection position. It can be positioned in the directional position. Furthermore, the dose setting member can be positioned at two different axial positions for dose setting and injection, respectively. The drive member can move axially with respect to the piston rod, but the axial movement of the drive member creates a risk that the dose can be inaccurate, as the drive member entrains the piston rod.

WO2004 / 078241A1 EP1804858B1 WO2008 / 145171A1 US8,096,978B2

  It is an object of the present invention to provide a drug delivery device with improved dose accuracy. Another object is to make a drug delivery device that is compact in size, preferably without components that translate out of the housing during dose setting. In addition, it is desirable to provide a component that is easily accessible by a device accessory, such as an electronic dose counter, at the appropriate location of the device.

  This object can be solved by a device as defined in claim 1.

  According to a first embodiment of the present invention, a hand-held injection device is operable on a housing, a rotatable dose setting member rotatable about a longitudinal axis of the housing, and a rotatable dose setting member. A powered reservoir in which energy is stored during rotation of the coupled, rotatable dose setting member and for receiving a force from one finger while the user is holding the injection device with the other finger of the hand A release member having a surface, a rotatably disposed drive member that at least partially engages at least a portion of a drive track of an associated piston rod, and rotationally constrained to the housing and releasable to the drive member Engaging release clutch. The release clutch is located in a first axial position when the release member is in the dose setting position, and the release clutch is further located in a second axial position when the release member is in the dose injection position. The drive member releases energy stored in the power reservoir when the release clutch is in its second axial position. The drive member is further adapted to rotate the associated piston rod when releasing the stored energy in the power reservoir. The axial position of the drive member within the housing remains constant when the release member is in its dose setting position and when the release member is in its dose injection position. In other words, the drive member is coupled and decoupled to the housing without any axial movement of the drive member itself. Preventing axial movement of the drive member between dose setting and dose dispensing (injection) helps to prevent unwanted axial movement of the piston rod. It is preferred if the device is suitable for dispensing user-selectable variable drug doses. The device may be a disposable device, ie a device that does not replace an empty cartridge.

  A locking arm that indicates a change in state (from dial setting to medication) can be provided near the outside of the device so that it can be easily accessed by a device accessory such as an electronic dose counter. The locking arm may be a component that is axially displaced between a (proximal) dose setting / dosing cancellation position and a (distal) dose dispensing position. Preferably the locking arm is part of a release clutch. In addition, this makes it easier to manufacture the housing with spline teeth on the locking arm rather than on the housing.

  Although it is generally possible to place a release member, such as a trigger, on the side of the housing, the release member may be located proximally adjacent to the rotatable dose setting member, eg, at the proximal end of the device. preferable.

  In order to prevent unintentional movement of the drive member during dose setting, a release clutch, which is constrained in the direction of rotation in the housing, is connected to the drive member so that the rotation of the drive member is engaged with the clutch. Can be blocked. For example, the release clutch can include at least one tooth or spline that engages a corresponding tooth or spline of the drive member when the release member is in its dose setting position.

  Preferably, the release clutch includes a locking arm that abuts the release member directly so that the release member entrains the locking arm when the release member moves in its dose injection position. In other words, when the user exerts a force on the release member from the finger, the release member is pushed in the distal direction, and the locking arm that abuts the release member in the axial direction is also pushed in the axial direction. The movement of the locking arm disengages the locking arm from the drive member, and the locking arm is then free to rotate under the action of the power reservoir.

  As an alternative, an injection device that includes a movable component located near the release member can indirectly engage the release clutch through this movable component. For example, a numerical sleeve can be provided that directly contacts the release member. The release clutch can include a locking arm that directly contacts the numeric sleeve such that the release member entrains the numeric sleeve and the locking arm when the release member moves in its dose injection position.

  Preferably, the injection device includes a piston rod having a threaded outer surface, and at least one drive track is disposed longitudinally of the outer surface of the piston rod. In addition, the drive member can engage at least a portion of the drive track of the piston rod. When the housing has a threaded portion that cooperates with the threaded outer surface of the piston rod, rotation of the piston rod can cause axial movement of the piston rod.

  According to another embodiment of the invention, the injection device further includes a gauge element that is rotationally constrained to the housing and axially displaceable relative to the housing. Thus, the position of the gauge element can be used to confirm the dose actually set and / or dispensed. The color of each section of the gauge member can make it easier to check the set and / or dispensed dose without reading numbers, symbols, etc. on the display.

  Preferably, the gauge element is threadedly engaged with a numeric sleeve or similar dose indicator such that rotation of the numeric sleeve causes an axial displacement of the gauge element relative to the numeric sleeve and the housing. The gauge element can have the shape of a shield or strip extending in the longitudinal direction of the device. As an alternative, the gauge element can be a sleeve.

  In an embodiment of the invention, the number sleeve is labeled with a series of numbers or symbols and the gauge element includes an opening or window. When the number sleeve is located radially inward of the gauge element, this allows at least one of the numbers or symbols on the number sleeve to be seen through the opening or window. In other words, a gauge element can be used to shield or cover a portion of the numeric sleeve so that only a limited portion of the numeric sleeve can be seen. This function may be added to the gauge element itself, which is suitable for identifying or displaying the actual set and / or dispensed dose.

  The power reservoir is preferably a torsion spring. Such torsion springs can be tensioned during dose setting. The spring is preferably preloaded and further tensioned by the user during dose setting. The stored energy is at least partially released during dose administration.

  According to a preferred embodiment, the drug delivery device includes a limiter mechanism that defines a maximum settable dose and a minimum settable dose. Typically, the minimum configurable volume is zero (0 IU for insulin formulations), so the limiter shuts off the device at the end of dose dosing. The maximum settable dose, such as 60, 80 or 120 IU of insulin formulation, is limited to avoid overdosing. Preferably, the minimum and maximum dose limits are provided by a hard stop function.

  The limiter mechanism includes a first rotation stop on the number sleeve and a first counter stop on the gauge element that abuts in a minimum dose (zero) position, and a second on the number sleeve that abuts in a maximum dose position. A rotation stop and a second counter stop on the gauge element. Because the number sleeve rotates relative to the gauge element during dose setting and dose dispensing, these two components are suitable for forming a reliable and robust limiter mechanism.

  In order to prevent underdosing or malfunction, the drug delivery device can include a final dose protection mechanism that prevents a dose from being set beyond the amount of liquid left in the cartridge. In a preferred embodiment, this final dose protection mechanism only detects the drug remaining in the cartridge when the dose contained in the cartridge is less than the maximum dose (eg, 120 IU).

  For example, the final dose protection mechanism includes a nut member positioned between the drive member and a component that rotates during dose setting and dose dispensing. The component that rotates during dose setting and dose dispensing may be a numeric sleeve or a dial sleeve that is constrained to the dose indicator in a rotational direction. In a preferred embodiment, the numeric sleeve and / or dial sleeve rotates during dose setting and dose dispensing, whereas the drive member rotates only during dose dispensing with the numeric sleeve and / or dial sleeve. Thus, in this embodiment, the nut member moves only during dose setting and remains stationary with respect to these components during dose dosing. Preferably, the nut member is threaded relative to the drive member and splined against the numeric sleeve and / or the dial sleeve. As an alternative, the nut member can be threaded on the numeric sleeve and / or dial sleeve and splined on the drive member. The nut member can be a full nut or a portion thereof, such as a half nut.

  A series of dose settings and dose dosing requires some relative movement of the components, either during dose setting and / or during dose dosing. A wide variety of embodiments are possible to achieve this result, some of which are described in the prior art described above. In accordance with a preferred embodiment of the present invention, the injection device can further include a clutch disposed between the drive member and the number sleeve, wherein the clutch is connected to the drive member and the number sleeve during dose setting. Relative rotation of the drive member and the number sleeve in the rotational direction during dose dosing. Alternative embodiments may include relative axial movement during dose setting, or articulation during dose setting followed by relative movement during dose dosing.

  The injection device can include at least one clicker mechanism for generating haptic and / or audible feedback. Preferably, the clicker mechanism signals the end of dose dosing. In a preferred embodiment of the present invention, the device comprises at least one first clicker that produces an audible and / or tactile first feedback during dose setting and / or dose dispensing, and the device has its minimum dose (zero). A second clicker that produces an audible and / or tactile second feedback different from the first feedback signal during dose dosing reaching position. The injection device can have separate clickers active during dose setting and during dose dosing.

The drug delivery device can include a cartridge that contains a medicament. The term “drug” as used herein means a pharmaceutical formulation comprising at least one pharmaceutically active compound,
Here, in one embodiment, the pharmaceutically active compound has a molecular weight of up to 1500 Da and / or a peptide, protein, polysaccharide, vaccine, DNA, RNA, enzyme, anti-housing or fragment thereof, A hormone or oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compounds,
Here, in a further embodiment, the pharmaceutically active compound is diabetic or diabetes related complications such as diabetic retinopathy, thromboembolism such as deep vein thromboembolism or pulmonary thromboembolism, acute coronary syndrome (ACS), useful for the treatment and / or prevention of angina pectoris, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and / or rheumatoid arthritis,
Here, in a further embodiment, the pharmaceutically active compound comprises at least one peptide for the treatment and / or prevention of diabetes-related complications such as diabetes or diabetic retinopathy,
Here, in a further embodiment, the pharmaceutically active compound is at least one human insulin or human insulin analogue or derivative, glucagon-like peptide (GLP-1) or analogue or derivative thereof, or exendin-3 or exendin -4 or exendin-3 or analogs or derivatives of exendin-4.

  Insulin analogues include, for example, Gly (A21), Arg (B31), Arg (B32) human insulin; Lys (B3), Glu (B29) human insulin; Lys (B28), Pro (B29) human insulin; Asp ( B28) human insulin; proline at position B28 is replaced with Asp, Lys, Leu, Val, or Ala, and at position B29, human insulin where Lys may be replaced with Pro; Ala (B26) human insulin; Des (B28-B30) human insulin; Des (B27) human insulin, and Des (B30) human insulin.

  Insulin derivatives include, for example, B29-N-myristoyl-des (B30) human insulin; B29-N-palmitoyl-des (B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28- N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N- (N-palmitoyl) -Des (B30) human insulin; B29-N- (N-ritocryl-γ-glutamyl) -des (B30) human insulin; B29-N- (ω- Carboxymethyl hepta decanoyl) -des (B30) human insulin, and B29-N- (ω- carboxyheptadecanoyl) human insulin.

  Exendin-4 is, for example, H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu Exendin-4 (1-39, which is a peptide of the sequence -Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 ).

Exendin-4 derivatives are, for example, compounds of the following list:
H- (Lys) 4-desPro36, desPro37 exendin-4 (1-39) -NH2,
H- (Lys) 5-desPro36, desPro37 exendin-4 (1-39) -NH2,
desPro36 exendin-4 (1-39),
desPro36 [Asp28] exendin-4 (1-39),
desPro36 [IsoAsp28] exendin-4 (1-39),
desPro36 [Met (O) 14, Asp28] exendin-4 (1-39),
desPro36 [Met (O) 14, IsoAsp28] Exendin- (1-39),
desPro36 [Trp (O2) 25, Asp28] exendin-4 (1-39),
desPro36 [Trp (O2) 25, IsoAsp28] exendin-4 (1-39),
desPro36 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39),
desPro36 [Met (O) 14Trp (O2) 25, IsoAsp28] Exendin-4 (1-39); or desPro36 [Asp28] Exendin-4 (1-39),
desPro36 [IsoAsp28] exendin-4 (1-39),
desPro36 [Met (O) 14, Asp28] exendin-4 (1-39),
desPro36 [Met (O) 14, IsoAsp28] Exendin- (1-39),
desPro36 [Trp (O2) 25, Asp28] exendin-4 (1-39),
desPro36 [Trp (O2) 25, IsoAsp28] exendin-4 (1-39),
desPro36 [Met (O) 14, Trp (O2) 25, Asp28] exendin-4 (1-39),
desPro36 [Met (O) 14, Trp (O 2) 25, IsoAsp 28] Exendin-4 (1-39),
(Wherein the group -Lys6-NH2 may be attached to the C-terminus of the exendin-4 derivative);

Or an exendin-4 derivative of the following sequence:
desPro36 exendin-4 (1-39) -Lys6-NH2 (AVE0010),
H- (Lys) 6-desPro36 [Asp28] Exendin-4 (1-39) -Lys6-NH2,
desAsp28Pro36, Pro37, Pro38 exendin-4 (1-39) -NH2,
H- (Lys) 6-desPro36, Pro38 [Asp28] Exendin-4 (1-39) -NH2,
H-Asn- (Glu) 5desPro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39) -NH2,
desPro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36 [Trp (O2) 25, Asp28] exendin-4 (1-39) -Lys6-NH2,
H-desAsp28Pro36, Pro37, Pro38 [Trp (O2) 25] exendin-4 (1-39) -NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) -NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39) -NH2,
desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39)-(Lys) 6-NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Trp (O2) 25, Asp28] exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36 [Met (O) 14, Asp28] exendin-4 (1-39) -Lys6-NH2,
desMet (O) 14, Asp28Pro36, Pro37, Pro38 exendin-4 (1-39) -NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2;
desPro36, Pro37, Pro38 [Met (O) 14, Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39)-(Lys) 6-NH2,
H-Asn- (Glu) 5desPro36, Pro37, Pro38 [Met (O) 14, Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H-Lys6-desPro36 [Met (O) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39) -Lys6-NH2,
H-desAsp28, Pro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25] exendin-4 (1-39) -NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Asp28] exendin-4 (1-39) -NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39) -NH2,
desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39)-(Lys) 6-NH2,
H- (Lys) 6-desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] Exendin-4 (S1-39)-(Lys) 6-NH2,
H-Asn- (Glu) 5-desPro36, Pro37, Pro38 [Met (O) 14, Trp (O2) 25, Asp28] Exendin-4 (1-39)-(Lys) 6-NH2;
Or a pharmaceutically acceptable salt or solvate of any one of the aforementioned exendin-4 derivatives.

  The hormones include, for example, gonadotropin (folytropin, lutropin, corion gonadotropin, menotropin), somatropin (somatropin), desmopressin, telluripressin, gonadorelin, triptorelin, leuprorelin, buserelin, nafarelin, goserelin, etc., Rote Liste, 2008 Pituitary hormones or hypothalamic hormones or regulatory active peptides and antagonists thereof.

  Polysaccharides include, for example, glucosaminoglycan, hyaluronic acid, heparin, low molecular weight heparin, or ultra low molecular weight heparin, or derivatives thereof, or sulfated forms of the above-described polysaccharides, such as polysulfated forms, and Or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of polysulfated low molecular weight heparin is sodium enoxaparin.

  Antibodies are globular plasma proteins (about 150 kDa), also known as immunoglobulins that share a basic structure. These are glycoproteins because they have sugar chains attached to amino acid residues. The basic functional unit of each anti-housing is an immunoglobulin (Ig) monomer (including only one Ig unit), and secretory antibodies are also dimers, bones with two Ig units such as IgA It can also be a tetramer with 4 Ig units, such as fish IgM, or a pentamer with 5 Ig units, such as mammalian IgM.

  An Ig monomer is a “Y” -shaped molecule composed of four polypeptide chains, two identical heavy chains and two identical light chains joined by a disulfide bond between cysteine residues. It is. Each heavy chain is about 440 amino acids long and each light chain is about 220 amino acids long. Each heavy and light chain contains intrachain disulfide bonds that stabilize these folded structures. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (eg, variable or V, and constant or C) based on their size and function. They have a characteristic immunoglobulin fold that creates a “sandwich” shape in which two β-sheets are held together by the interaction between conserved cysteines and other charged amino acids.

  There are five types of mammalian Ig heavy chains represented by α, δ, ε, γ and μ. The type of heavy chain present defines the anti-housing isotype, and these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.

  Different heavy chains differ in size and composition, α and γ contain about 450 amino acids, δ contain about 500 amino acids, and μ and ε have about 550 amino acids. Each heavy chain has two regions: a constant region (CH) and a variable region (VH). In one species, the constant region is essentially the same for all antibodies of the same isotype, but different for antibodies of different isotypes. Heavy chains γ, α, and δ have a constant region composed of three tandem Ig domains and a hinge region to add flexibility, and heavy chains μ and ε are four immunoglobulins -It has a constant region composed of domains. The variable region of the heavy chain is different for antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.

  In mammals, there are two types of immunoglobulin light chains, denoted λ and κ. The light chain has two consecutive domains, one constant domain (CL) and one variable domain (VL). The approximate length of the light chain is 211-217 amino acids. Each anti-housing has two light chains that are always identical, and there is only one type of light chain κ or λ for each mammalian anti-housing.

  Although the general structure of all antibodies is very similar, the unique properties of a given anti-housing are determined by the variable (V) region, as detailed above. More specifically, three variable loops for each light chain (VL) and three variable loops in the heavy chain (HV) are involved in antigen binding, ie its antigen specificity. These loops are called complementarity determining regions (CDRs). Since CDRs from both the VH and VL domains contribute to the antigen binding site, it is the combination of heavy and light chains that determines the final antigen specificity, not either alone.

  An “anti-housing fragment” comprises at least one antigen-binding fragment as defined above and exhibits essentially the same function and specificity as the complete anti-housing from which the fragment is derived. Limited protein digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one complete light chain and about half the heavy chain, are antigen-binding fragments (Fabs). A third fragment that is equivalent in size but contains a carboxyl terminus at half the positions of both heavy chains with interchain disulfide bonds is a crystallizable fragment (Fc). Fc includes a carbohydrate, a complementary binding site, and an FcR binding site. Limited pepsin digestion yields a single F (ab ') 2 fragment containing both the Fab piece and the hinge region containing the H-H interchain disulfide bond. F (ab ') 2 is divalent for antigen binding. The disulfide bond of F (ab ') 2 can be cleaved to obtain Fab'. In addition, the variable regions of the heavy and light chains can be condensed to form a single chain variable fragment (scFv).

  Pharmaceutically acceptable salts are, for example, acid addition salts and basic salts. Examples of acid addition salts include HCl or HBr salts. The basic salt is, for example, a cation selected from alkali or alkaline earth such as Na +, or K +, or Ca2 +, or ammonium ions N + (R1) (R2) (R3) (R4) (wherein R1 ~ R4 are independently of each other: hydrogen, optionally substituted C1-C6 alkyl group, optionally substituted C2-C6 alkenyl group, optionally substituted C6-C10 aryl group, or optionally substituted C6- Meaning a C10 heteroaryl group). Additional examples of pharmaceutically acceptable salts can be found in “Remington's Pharmaceutical Sciences” 17th edition, Alfonso R. et al. Gennaro (eds.), Mark Publishing Company, Easton, Pa. U. S. A. 1985, and Encyclopedia of Pharmaceutical Technology.

  A pharmaceutically acceptable solvate is, for example, a hydrate.

  Next, non-limiting exemplary embodiments of the present invention will be described with reference to the accompanying drawings.

1 is an exploded view of components of an injection device according to a first embodiment of the present invention. FIG. FIG. 2 is a perspective view of the device of FIG. FIG. 2 is a cross-sectional view of the device of FIG. FIG. 2 is an enlarged view of details of the device of FIG. FIG. 2 is an enlarged view of details of the device of FIG. FIG. 2 is an enlarged cross-sectional view of details of the device of FIG. FIG. 2 is a cross-sectional view of the device of FIG. 1 in a stationary state. FIG. 2 is a cross-sectional view of the device of FIG. 1 in an activated state. FIG. 2 is an enlarged cross-sectional view of details of the device of FIG. FIG. 6 is a cross-sectional view of an injection device according to a second embodiment of the invention in a stationary state. FIG. 11 is a cross-sectional view of the device of FIG. 10 in an activated state.

  FIG. 2 shows a drug delivery device in the form of an injection pen. The device has a distal end (upper end in FIG. 2) and a proximal end (lower end in FIG. 2). The component members of the drug delivery device are shown in FIG. The drug delivery device includes a housing 10, a cartridge holder 20, a lead screw (piston rod) 30, a driver 40, a nut 50, a dial sleeve 60, a button 70, a dose selector 80, a torsion spring 90, a locking arm 100, a gauge element 110, a dose. An indicator (numeral sleeve) 120, a clutch plate 130, a clutch spring 140, a return spring 150, a support portion 160, and a cartridge 170 are included. A needle arrangement (not shown) with a needle hub and needle cover is provided as an additional component that can be replaced as described above.

  The housing 10 or body is a generally tubular element. In the illustrated embodiment, the housing 10 allows viewing of the liquid drug cartridge 170 and cartridge holder 20, the interface that constrains the locking arm 100 in the rotational direction, and the dose number on the dose indicator 120. A place is provided for the slot 11 or the lens and the function for holding the dose selector 80 axially on its outer surface, for example an outer circumferential groove. The flanged inner wall 12 includes an inner thread that engages the piston rod 30. Further, the clicker arm 13 or beam is incorporated into the housing 10 for interaction with the driver 40.

  The cartridge holder 20 is located on the distal side of the housing 10. The cartridge holder can be a tubular transparent or translucent component for receiving the cartridge 170. The distal end (upper end in FIG. 2) of the cartridge holder 20 can be provided with means for attaching the needle arrangement. A removable cap (not shown) is provided to fit over the cartridge holder 20 and is held by a clip function.

  The lead screw 30 is an elongated member with an outer thread 31 that is constrained to the driver 40 in the rotational direction via a splined interface. The interface includes at least one longitudinal groove or track 32 and a corresponding driver projection 40 or spline 44. When rotating, the lead screw 30 is forced to move axially relative to the driver 40 by a threaded interface with the housing 10.

  The driver 40 is a sleeve that extends from the interface with the dial sleeve 60 to the splined interface 41 with the locking arm 100 via the clutch plate 130. This sleeve provides a constraint in the direction of rotation of the locking arm 100 relative to the driver 40 during dose setting. When the dose button 70 is pressed, these spline teeth are disengaged and the driver 40 can rotate. In addition, teeth 42 are provided on the proximal end face of the driver 40 for engagement with the clutch plate 130. The driver 40 has a threaded section 43 that provides a helical track for the nut 50. In addition, a final dose abutment is provided, which can be the end of the track of the thread 43 or, preferably, a hard rotation stop that limits the movement of the nut 50 on the thread 43.

  The nut 50 is part of the final dose limiter mechanism. The nut 50 is located between the dial sleeve 60 and the driver 40. This nut is constrained in the rotational direction to the dial sleeve 60 via a splined interface. The nut moves along a helical path relative to the driver 40 via the threaded interface when relative rotation occurs between the dial sleeve 60 and the driver 40 during dial setting. As an alternative, the nut 50 is splined with respect to the driver 40 and threaded with respect to the sleeve 60. In the embodiment of FIGS. 1-9, nut 50 is a half nut, i.e., it is a component that extends approximately 180 [deg.] About the central axis of the device. Alternatively, if the driver 40 is formed from two separate components that engage tightly when assembled, the nut 50 can also be a complete nut.

  The dial sleeve 60 is a tubular element. The dial sleeve receives the clutch plate 130 and the proximal end of the driver 40 to which the dial sleeve is coupled via the clutch plate. The distal end of the dial sleeve 60 is permanently constrained to the dose indicator 120. For manufacturing reasons, the dial sleeve 60 and the dose indicator 120 are separate components. However, they can also be integrated into a single component member.

  Button 70 forms the proximal end of the device. The button 70 has an annular skirt 71 that is received in the dose selector 80. In addition, the button 70 has a proximal end plate on which the button cover rests, as shown in FIG. The dose button 70 is permanently splined to the dose selector 80 and is splined to the dial sleeve 60 by the respective spline function 71, 72 when the button 70 is not pressed. The splined interfaces 71 and 72 are separated when the dose button 70 is pressed. Dose dosing is initiated by actuation of the dose button 70. FIG. 6 shows the spline function 72 as a tooth, which also engages or engages with the corresponding teeth on the inner surface of the dose selector 80 and the outer surface of the dose dial sleeve 60, respectively. It can be designed so that it can be released.

  The dose selector 80 or dose dial grip is a sleeve-like component with a serrated outer skirt. The dose selector 80 is axially constrained relative to the housing 10. The dose selector is rotationally constrained to the dose button 70 via a splined interface. This splined interface remains engaged regardless of the axial position of the dose button 70.

  The torsion spring 90 is attached to the housing 10 at one end and to the dose indicator 120 at the other end. The torsion spring 90 is pre-wound during assembly so that the torsion spring torques the dose indicator 120 when the mechanism is dialed in zero units. Turning the dose selector 80 to set the dose causes the dose indicator 120 to rotate relative to the housing 10 and charge the torsion spring 90. A torsion spring 90 is located inside the dose indicator 120 and surrounds the distal portion of the driver 40.

  The locking arm 100 is rotationally fixed to the housing 10 but can be translated in the axial direction. An axial movement is provided by a dose button 70 whose distal surface abuts the proximal surface of the locking arm 100. The locking arm 100 has teeth 101 near its distal end for releasably connecting the toothed interface 41 of the driver 40 to the housing 10 via the locking arm 100.

  Gauge element 110 is a window element that is forced to prevent rotation but allow translational motion relative to housing 10 via a splined interface. This is also threadedly engaged with the dose indicator 120 such that rotation of the dose indicator 120 causes an axial translational movement of the gauge element 110. Gauge element 110 has a spiral cut in its inner surface that provides a gap in the stop feature on dose indicator 120 as gauge element 110 moves axially laterally during numeric sleeve rotation. The gauge element 110 is located in the housing 10 so that it is guided in the slot 11 and closes the slot. The gauge element is generally a plate-like or strip-like component having a central opening 111 or window and two flanges 112, 113 extending on either side of the opening. The flanges 112, 113 are preferably not transparent and thus shield or cover the dose indicator 120, while the opening 111 or window allows the portion of the numeric sleeve to be seen. In addition, the gauge element 110 has an arm 114 that interacts with the dose indicator 120 at the end of dose dosing. Gauge element 110 is shown in more detail in FIG.

  The dose indicator 120 is a numeric sleeve that is rotationally constrained to the dial sleeve 60 via a splined interface. They are constrained to the housing 10 so that they can rotate but not translate. The dose indicator 120 is numbered with a series of numbers visible through the central opening 111 of the gauge element 110 and the slot 11 of the housing 10 to indicate the dialed dose of the drug. Lock ring 121 is firmly bound to dose indicator 120. This ring is only a separate component to simplify the number sleeve mold set. The dose indicator 120 has a beveled rotation stop 122 that abuts the side of the gauge element 110 at a position where the zero unit dose is dialed (minimum dose position). A similar stop is provided on the opposite side of the dose indicator 120 to prevent setting a dose that exceeds the maximum dose, for example, more than 120 units. A flexible arm 123 is provided that interacts with the arm 114 of the gauge element 110 at the end of dose dosing.

  Clutch plate 130 is splined with respect to dial sleeve 60. The clutch plate is also coupled to the driver 40 via ratchet interfaces 42, 131, which is done by axial contact. The ratchets 42, 131 provide detent positions between the dial sleeve 60 and the driver 40 corresponding to each dose unit and engage with different inclined tooth angles during clockwise and counterclockwise relative rotation. FIG. 6 shows the clutch plate 130 in more detail with the proximal end of the device.

  The clutch spring 140 is located between the button 70 and the clutch plate 130. The clutch spring acts on the clutch plate to allow the ratchet teeth 42, 131 to collide with each other against the spring axial force during dose setting.

  The return spring 150 acts against the locking arm 100 to force the spline teeth 101 into engagement with the teeth 41 of the driver 40.

  The support portion 160 is restrained in the axial direction by the lead screw 30 and acts on the stopper in the liquid medicine cartridge 170.

  The cartridge 170 is received in the cartridge holder 20. The cartridge 170 can be a glass ampoule having a movable rubber plug 171 at its proximal end. The distal end of the cartridge 170 is provided with a pierceable rubber seal that is held in place by a crimped annular metal band. In the illustrated embodiment, the cartridge 170 is a standard 1.5 ml cartridge. The device is designed to be disposable because the cartridge 170 is not replaceable by the user or medical professional. However, it is also possible to provide a reusable variant of the device by making the cartridge holder 20 removable and allowing the lead screw 30 to be unwound and the nut 50 to be reset.

  The axial position of the locking arm 100, clutch plate 130 and dose button 70 is defined by the action of a return spring 150 and clutch spring 140 that applies a force proximally to the locking arm 100 and dose button 70. This ensures that the spline of the dose button 70 engages the dial sleeve 60 and the teeth 41 of the driver 40 engage the locking arm 100 in the “stationary” position (shown in FIG. 2). become.

  In the following, the function of the disposable drug delivery device and its components will be described in more detail.

  When the device is stationary as shown in FIG. 2, the dose indicator 120 is positioned against the dose indicator zero dose abutment (FIG. 4) with the gauge element 110 and the dose button 70 is Not pushed down. A dose mark “0” on the dose indicator 120 is visible through the window of the housing 10 and the central opening 111 of the gauge element 110. The torsion spring 90 applied with several pre-wound turns when the device is assembled applies a certain torque to the dose indicator 120 and is not rotated by the zero dose abutment 122. It is also possible to slightly “rewind” the mechanism by an offset between the zero dose stop 122 and the angular offset of the spline teeth 41 of the drive 40. This has the effect of preventing dripping that can occur when the dose is dialed and the zero dose abutment is disengaged.

  The user selects a variable dose of liquid medication by turning the dose selector 80 clockwise, and this rotation causes an equivalent rotation of the dial sleeve 60 and thus the dose indicator 120. The rotation of the dose indicator 120 causes the torsion spring 90 to charge, increasing the energy stored in the spring. As the dose indicator 120 rotates, the gauge element 110 translates axially due to its screw engagement, thereby indicating a dialed dose value. As described above, the gage element 110 has flanges 112, 113 on either side of the central opening 111 that may have a visual difference to provide additional feedback for the dial set dose value / delivery dose value. Have In the embodiment of FIGS. 1-9, a dose selector 80 is utilized that is increased in diameter relative to the housing 10 to aid in dial setting. The driver 40 is prevented from rotating by the engagement between the spline teeth 41 and the locking arm 100. Accordingly, relative rotation must occur between the clutch plate 130 and the driver 40 via the ratchet interface 42,131.

  The user torque required to turn the dose selector 80 is the sum of the torque required to wind up the torsion spring 90 and the torque required to loosen the ratchet function 42,131. The clutch spring 140 is designed to provide axial force to the ratchet function and to bias the clutch plate 130 over the drive 40. This axial load acts to maintain the ratchet teeth engagement between the clutch plate 130 and the driver 40. The torque required to loosen the ratchets 42, 131 is a result of the axial load applied by the clutch spring 140, the clockwise slope angle of the ratchets 42, 131, the coefficient of friction between the coupling surfaces, and the average radius of the ratchet function. As obtained.

  When the user turns the dose selector 80 enough to increment the mechanism by one unit, the dial sleeve 60 rotates relative to the driver 40 by one ratchet tooth. At this point, the ratchet teeth 42, 131 are reengaged at the next detent position. An audible click is produced by ratchet re-engagement and tactile feedback is provided by the required change in torque input.

  The relative rotation of the dial sleeve 60 and the driver 40 also causes the nut 50 to move along the threaded path over the driver 40 toward its final dose abutment.

  The user torque is not applied to the dose selector 80 and the dial sleeve 60 is now rotated by the action of the torque applied by the torsion spring 90 due to the engagement of the ratchets 42, 131 between the clutch plate 130 and the driver 40. Is only blocked. The torque required to loosen the ratchets 42, 131 counterclockwise is the axial load applied by the clutch spring 90, the ratchet counterclockwise slope angle, the coefficient of friction between the coupling surfaces, and the average radius of the ratchet function. As a result of The torque required to loosen the ratchets 42, 131 must be greater than the torque applied to the dial sleeve 60 by the torsion spring 90, and thus the torque applied to the clutch plate 130. Thus, to ensure that the ratchet ramp angle is increased counterclockwise while ensuring that the dial set torque is as small as possible.

  The user can now choose to increase the selected dose by continuing to rotate the dose selector 80 clockwise. The process of loosening the ratchet interface between the dial sleeve 60 and the driver 40 is repeated for each dose unit. Additional energy is stored in the torsion spring 90 for each dose unit, and audible and tactile feedback is provided for each unit dialed by re-engagement of the ratchet teeth 42,131. The torque required to turn the dose selector 80 increases as the torque required to wind up the torsion spring 90 increases. Accordingly, the torque required to loosen the ratchets 42, 131 counterclockwise must be greater than the torque applied to the dial sleeve 60 by the torsion spring 90 when the maximum dose is reached.

  If the user continues to increase the selected dose until the maximum dose limit is reached, the dose indicator 120 will engage its maximum dose abutment on the gauge element 110. This prevents further rotation of the dose indicator 120, dial sleeve 60, clutch plate 130, and dose selector 80. Depending on how many units have already been delivered by the mechanism, the nut 50 can contact its final dose abutment with the drive 40 during dose selection. This abutment further prevents further relative rotation of the dial sleeve 60 and the drive 40, thus limiting the capacity that can be selected. The position of the nut 50 is determined by the total number of relative rotations between the dial sleeve 60 and the drive 40 that occur each time the user sets the dose.

  If there is a mechanism in which a dose is selected, the user can deselect any number of units from this dose. Deselecting a dose is accomplished by the user turning the dose selector 80 counterclockwise. The torque applied by the user to the dose selector 80, when combined with the torque applied by the torsion spring 90, is sufficient to loosen the ratchets 42, 131 between the clutch plate 130 and the drive 40 in a counterclockwise direction. When the ratchet is loosened, a counterclockwise rotation through the clutch plate 130 occurs in the dial sleeve 60, which causes the dose indicator 120 to return toward the zero dose position and the torsion spring 90 to unwind. The relative rotation between the dial sleeve 60 and the driver 40 causes the nut 50 to be returned from the final dose abutment over the driver 40 along its helical path (thread 43).

  If the mechanism is in a state where a dose is selected, the user can activate the mechanism and begin delivering the dose. Dose delivery is initiated by the user depressing the dose button 70 at the proximal end of the device. 7 and 8 show the device in two positions with the dose button 70 stationary (FIG. 7) and the dose button 70 depressed (FIG. 8). When the dose button 70 is depressed, the dial sleeve 60 and splines 71, 72 to the dose button 70 are disengaged and the dose selector 80 is rotationally separated from the delivery mechanism so that the dose selector 80 does not rotate during dosing. become. The dose button 70 acts on the locking arm 100 which moves to separate the spline tooth engagement 41, 101 for the driver 40. Driver 40 can now rotate and is driven by torsion spring 90 through dose indicator 120, dial sleeve 60 and clutch plate 130. The rotation of the driver 40 causes the lead screw 30 to rotate by these spline engagements, and then the lead screw 30 is advanced by screw engagement with the housing 10. The rotation of the number sleeve also moves the gauge element 110 laterally back to its zero position, whereby the zero dose abutment 122 stops the mechanism.

  Tactile feedback during delivery is provided via a compliant cantilever beam 13 that is axially joined to the spline teeth 41 of the driver 40 integrated in the housing 10 so that the spline tooth spacing is a single unit dose. This corresponds to the rotation of the driver 40 necessary for the above. As the driver 40 rotates during dosing, the spline function 41 engages the clicker arm 13 to generate an audible click sound each time a dose unit is delivered. Dose delivery continues with the mechanical interaction described above while the user continues to depress the dose button 70.

  When the user releases the dose button 70, the clutch spring 140 and return spring 150 cooperate to return the dose button to its rest position. The return spring 150 acts on the dose button 70 via the locking arm 100 and therefore also translates axially. As the locking arm 100 returns toward its rest position, the spline 101 engages the spline feature 41 of the driver 40 to constrain the driver 40 in the rotational direction relative to the housing 10 and stop delivering the dose.

  During the delivery of the dose, the driver 40 and dial sleeve 60 rotate together so that no relative movement of the nut 50 occurs. Therefore, the nut 50 moves on the driver 40 toward the contact portion only during dial setting.

  When dose delivery is stopped by returning the dose indicator 120 to the zero dose abutment, the user can release the dose button 70, which will re-lock the spline teeth of the locking arm 100 to the driver 40. Will be engaged. Here, the mechanism is returned to a stationary state.

  It is possible to angle the spline teeth 41, 101 with either or both of the driver 40 and the locking arm 100 so that when the dose button 70 is released, the re-engagement of the spline teeth will cause the driver 40 to partially In particular, “rewinding”, thereby disengaging the dose indicator 120 from the zero dose stop abutment 122 of the gauge element 110. This can result in a slight advancement of lead screw 30 and medication dosing when the next dose is dialed into the device if not removed (due to the zero dose abutment 122 of dose indicator 120 no longer constraining the mechanism). Rather, the effect of mechanism clearance (eg due to tolerances) is eliminated, due to the restraint return to the spline between the drive sleeve and the locking arm 100.

  At the end of the dose, additional audible and / or tactile feedback is provided in the form of a click sound different from the click sound provided during medication to inform the user that the device has returned to the zero position. . This is accomplished by the interaction of three components: the dose indicator 120, the gauge element 110 and the locking arm 100. This embodiment allows feedback to be generated only at the end of dose delivery and not if the device is dialed into or out of the original zero position. FIG. 4 shows the position of each function when the dose is dialed. It can be seen in the figure that the locking arm 100 does not contact the flexible arm 123 of the dose indicator 120 and therefore the flexible arm 123 is not deflected during dial setting. However, during dose delivery, the locking arm 100 is in an axially advanced (distal) position, thereby axially deflecting the flexible arm 123 of the numeric sleeve. As can be seen in FIG. 4, the locking arm 100 has a notch or slot with a distal surface 102, which is when the locking arm 100 is displaced distally when the button 70 is depressed. , Interacts with the protrusion 124 of the arm 123. In this way, the flexible arm 123 on the dose indicator 120 is axially moved by the locking arm 100 only when the dose button 70 is depressed, i.e. during dose administration, not during dose setting or dose cancellation. To be biased. When the dose indicator 120 returns to its zero position, the flexible arm 123 contacts another protrusion 125 of the semi-flexible arm 114 of the gauge element 110. In the zero position, the flexible arm 123 overlies the arm 114 of the gauge element 110 to produce a unique click sound feedback. In the embodiment of FIG. 4, the arm 114 has a recess 115 into which the protrusion 125 clicks to increase audible and / or tactile feedback at the zero position.

  A second, alternative embodiment is shown in FIGS. Similar to the first embodiment, the device of this second embodiment has a dose button 70 at its proximal end. This device features a translational dose indicator 120 for activating the device during dose dispensing. In other words, the device utilizes the axial process of the dose indicator 120 upon actuation of the dose button 70 to release the drive 40 from the rotational lock with the housing 10. This reduces the outer diameter and length of the mechanism. FIG. 10 shows the device in a stationary position, whereas in FIG. 11, the dose button 70 is depressed. The function of the component mainly corresponds to the first embodiment.

  In this second embodiment, the dose button 70 has an axial abutment with the dose indicator 120. Due to the length of the dose indicator 120, the separate dial sleeve of the first embodiment is omitted. In its distal region, the dose indicator 120 acts against a separate locking arm 230 that is splined to the housing 10 and has teeth that engage the corresponding teeth 41 of the driver 40. . Thus, as dose indicator 120 moves axially when dose button 70 is depressed, locking arm 230 is forced to move axially and disengage from driver 40, and torsion spring 90 delivers the dose. It becomes possible. Similarly, when the dose button 70 is released, the dose indicator 120 and the locking arm 230 return to their original axial position under the action of the axial spring 240 and the driver 40 is locked again against rotation. .

  Since the gauge element 110 is threaded with respect to the dose indicator 120, it moves axially with the dose indicator 120 when the dose button 70 is depressed and released, thus the gauge element 110 and the housing 10 The lens or slot 11 always remains centered with the dose indicator 120 so that the correct dose is displayed.

  An additional spring 240 acts on the distal end of the dose indicator 120 to bias the mechanism in a stationary position, i.e. in the proximal position of the number sleeve. For manufacturing reasons, the driver 40 may include two component members that are rigidly secured, as shown in FIGS. The nut 50 is located between the driver 40 and the (extension) dose indicator 120.

  The dose indicator 120 translates axially by actuation of the dose button 70, but there is no axial movement of the dose indicator 120 during dose setting or dose dosing.

  As can be appreciated from the description of the above three embodiments, the important features and advantages of the present invention include:

  The set dose and / or the remaining dose are displayed through an axially moving window in the device-"Gauge" function. This feature provides additional visual dose transition feedback. This feedback can be enhanced if either side of the window 111, i.e. the flanges 112, 113, has a function such as another color and / or indicia.

  The dose indicator 120 does not translate helically in any embodiment.

  The end button mechanism of the embodiment has a large dose selector 80 to aid in dose setting.

  A dose end click is incorporated into each mechanism that is activated during dose delivery but not during dose selection or dose cancellation.

  There is an alternative third embodiment to the end button of the first embodiment, whereby the dose indicator 120 moves axially during activation and release of the dose button 70 but during dose delivery. Does not move.

  Each of the above features is distinct from other features and is distinct from internal features of other component members such as clutches, ratchets, clickers, dose displays or drive means.

  Another common feature of all embodiments is that the device does not have a dial extension, i.e. the length of the device is the same whether the dose is dialed or not. In addition, the dose selector 80 does not rotate during dosing and is shaped to make dial setting easier (flat or larger in diameter). Gauge element 110 provides the user with qualitative feedback about the course of dose. This is particularly important for blind users who may have difficulty identifying individual numbers or symbols on a number sleeve. All of these features should bring great ergonomic benefits to the user.

Claims (13)

A hand-held injection device,
A housing (10);
A dose setting member (80, 60) rotatable about a longitudinal axis of the housing (10);
A power reservoir (90) operably coupled to the dose setting member (80, 60) and storing energy during rotation of the dose setting member (80, 60);
A release member (70) having a surface for receiving a force from one finger while the user is holding the injection device with the other finger of the hand;
A rotatably disposed drive member (40) that at least partially engages at least a portion of a drive track (32) of an associated piston rod (30);
Release clutches (100, 230) constrained in a rotational direction to the housing (10) and releasably engaged with the drive member (40);
A number sleeve (120) in direct contact with the release member (70);
Here, the drive member (40) releases energy stored in the power reservoir (90) when the release clutch (100) is in its second axial position, and the drive member (40) Applied to rotate the associated piston rod (30) when releasing the stored energy in the power reservoir (90);
Here, the release clutch (100, 230) can be positioned in the first axial position when the release member (70) is in the dose setting position, and the release clutch (100, 230) further includes a release member ( 70) can be positioned in the second axial position when in the dose injection position, and the axial position of the drive member (40) in the housing (10) is such that the release member (70) is in its dose setting position. Sometimes also remains constant when the release member (70) is in its dose injection position,
Here, the release clutch attaches to the number sleeve (120) such that the release member (70) entrains the number sleeve (120) and the locking arm (100) when the release member (70) moves in its dose injection position. Including a locking arm (230) that abuts directly;
Said injection device. The injection device according to claim 1, wherein the release member (70) is located proximally adjacent to the rotatable dose setting member (80, 60).   The release clutch (100, 230) includes at least one tooth (101) or spline that engages a corresponding tooth (41) or spline of the drive member (40) when the release member (70) is in its dose setting position. The injection device according to claim 1, comprising:   The number sleeve (120) further includes a dose setting member (80, 60) operably coupled to the number sleeve (120), the dose setting member (80, 60) and the number sleeve (120) being an injection. Working together to set the dose to be ejected from the device, the numeric sleeve (120) is adapted to have a simple rotational movement with respect to the housing (10) within the housing (10) during dose setting. The injection device according to any one of claims 1 to 3.   The housing (10) has a threaded portion (12) that cooperates with a threaded outer surface (31) of the piston rod (30) such that rotation of the piston rod (30) results in axial movement of the piston rod (30). The injection device according to claim 1, comprising:   The injection device according to any one of the preceding claims, further comprising a gauge element (110) constrained in the rotational direction to the housing (10) and axially displaceable relative to the housing (10).   Gauge element (110) is threadedly engaged with numeric sleeve (120) such that rotation of the dose indicator causes axial displacement of gauge element (110) relative to numeric sleeve (120) and housing (10). The injection device according to claim 6.   The number sleeve (120) is labeled with a series of numbers or symbols, the gauge element (110) includes an opening or window (111), and the number sleeve (120) is a number or symbol on the number sleeve (120). The injection device according to claim 6 or 7, wherein the injection device is located radially inward of the gauge element (110) such that at least one of them is visible through an opening or window (111). The injection device according to any of the preceding claims, wherein the power reservoir (90) is a torsion spring that tensions during dose setting.   Limiter mechanisms (122, 110) that define maximum and minimum settable doses, and / or a final dose protection mechanism (40, 40) that prevents a dose from being set beyond the amount of liquid left in the cartridge (170). The injection device according to any one of claims 1 to 9, comprising 50, 60; 120).   The clutch further includes a clutch (130) disposed between the drive member (40) and the dose indicator (120), wherein the clutch is relative to the drive member (40) and the dose indicator (120) during dose setting. 11. An injection device according to any one of the preceding claims, which allows rotation and constrains the drive member (40) and the dose indicator (120) in a rotational direction during dose dispensing. At least one first clicker (42, 131, 41, 13, 41, 192) that produces audible and / or tactile first feedback during dose setting and / or during dose administration, and the device has its minimum dose A second clicker (114, 123) that produces an audible and / or tactile second feedback different from the first feedback signal during dose dosing reaching a (zero) position. The injection device according to any one of 11.   The injection device according to any one of the preceding claims, further comprising a cartridge (170) for containing a medicament.

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